Growth hormone-releasing hormone: not only a neurohormone.
ABSTRACT Growth hormone-releasing hormone (GHRH) is mostly thought to act by stimulating the production and release of growth hormone from the pituitary. However, this neuropeptide emerges as a rather pleiotropic hormone in view of the identification of various extrapituitary sources for GHRH production, as well as the demonstration of a direct action of GHRH on several tissues other than the pituitary. Non-pituitary GHRH has a wide spectrum of activity, exemplified by its ability to modulate cell proliferation, especially in malignant tissues, to regulate differentiation of some cell types, and to promote healing of skin wounds. These findings extend the role of GHRH and its analogs beyond its accepted regulation of somatotropic activity and indicate new possibilities for therapeutic intervention.
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ABSTRACT: We outline an in vivo cellular program of bovine longissimus muscle development inferred from expression data from 60days post conception to 3months postnatal. Analytic challenges included changes in cellular composition, ambiguous 'diagnostic' markers of cell type and contrasts between cattle human and mouse myogenesis. Nevertheless, the expression profiles of the myosin isoforms support slow and fast muscle fibres emanating from primary and secondary myogenesis respectively, while expression of the prenatal myosin subunits is down regulated prior to birth. Of the canonical pro-myogenic transcription factors (TF), MYF6 and MYF5 are negatively co-expressed, with MYF6 displaying higher expression in the post-natal samples and MYF5, MYOG, HES6 and PAX7 displaying higher expression in early development. A set of TFs (SIX1, EYA2 and DACH2) considered important in undifferentiated murine cells were equally abundant in differentiated bovine cells. An examination of mammalian regulators of fibre composition, muscle mass and muscle metabolism, underscored the roles of PPARGC1A, TGFβ signalling and the NHR4 Nuclear Hormone Receptors on bovine muscle development. Enriched among the most variably expressed genes from the entire data set were molecules regulating mitochondrial metabolism of carbohydrate (PDK4), fat (UCP3), protein (AGXT2L1) and high energy phosphate (CKMT2). The dramatic increase in the expression of these transcripts, which may enable the peri-natal transition to metabolic independence critical for new-born herbivores, provides surprising evidence for substantial developmental remodelling of muscle mitochondria and reflects changes in nutrient availability. Overall, despite differences in size, metabolism and physiology, the muscle structural subunit expression program appears very similar in ruminants, rodents and humans.Gene Expression Patterns 02/2013; · 1.64 Impact Factor
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ABSTRACT: Goldfish GH-releasing hormone (gGHRH) has been recently identified and shown to stimulate GH release in goldfish. In goldfish, neuroendocrine regulation of GH release is multifactorial and known stimulators include goldfish ghrelin (gGRLN19) and salmon gonadotropin-releasing hormone (sGnRH), factors that also enhance LH secretion. To further understand the complex regulation of pituitary hormone release in goldfish, we examined the interactions between gGHRH, gGRLN19, and sGnRH on GH and LH release from primary cultures of goldfish pituitary cells in perifusion. Treatment with 100 nM gGHRH for 55 min stimulated GH release. A 5-min pulse of either 1 nM gGRLN19 or 100 nM sGnRH induced GH release in naïve cells, and these were just as effective in cells receiving gGHRH. Interestingly, gGHRH abolished both gGRLN19- and sGnRH-induced LH release and reduced basal LH secretion levels. These results suggest that gGHRH does not interfere with sGnRH or gGRLN19 actions in the goldfish somatotropes and further reveal, for the first time, that GHRH may act as an inhibitor of stimulated and basal LH release by actions at the level of pituitary cells.General and Comparative Endocrinology 03/2013; · 2.82 Impact Factor
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ABSTRACT: The dismal prognosis of malignant brain tumors drives the development of new treatment modalities. In view of the multiple activities of growth hormone-releasing hormone (GHRH), we hypothesized that pretreatment with a GHRH agonist, JI-34, might increase the susceptibility of U-87 MG glioblastoma multiforme (GBM) cells to subsequent treatment with the cytotoxic drug, doxorubicin (DOX). This concept was corroborated by our findings, in vivo, showing that the combination of the GHRH agonist, JI-34, and DOX inhibited the growth of GBM tumors, transplanted into nude mice, more than DOX alone. In vitro, the pretreatment of GBM cells with JI-34 potentiated inhibitory effects of DOX on cell proliferation, diminished cell size and viability, and promoted apoptotic processes, as shown by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide proliferation assay, ApoLive-Glo multiplex assay, and cell volumetric assay. Proteomic studies further revealed that the pretreatment with GHRH agonist evoked differentiation decreasing the expression of the neuroectodermal stem cell antigen, nestin, and up-regulating the glial maturation marker, GFAP. The GHRH agonist also reduced the release of humoral regulators of glial growth, such as FGF basic and TGFβ. Proteomic and gene-expression (RT-PCR) studies confirmed the strong proapoptotic activity (increase in p53, decrease in v-myc and Bcl-2) and anti-invasive potential (decrease in integrin α3) of the combination of GHRH agonist and DOX. These findings indicate that the GHRH agonists can potentiate the anticancer activity of the traditional chemotherapeutic drug, DOX, by multiple mechanisms including the induction of differentiation of cancer cells.Proceedings of the National Academy of Sciences 12/2013; · 9.81 Impact Factor